Benzodiazepines (BZDs) are a class of drugs that are act upon the central nervous system. They are employed clinically as sedatives-anxiolytic drugs (Goodman & Gilman Chapter 16) (Katzung Chapter 22); therapy for epilepsies [Article:19674049] (Goodman & Gilman Chapter 19, Katzung Chapter 24); panic disorders (Goodman & Gilman Chapter 17) and various other disorders such as Familial paroxysmal choreoathetosis [Article:17515540] and Hyperexplexia (Startle syndrome) [Articles:16236274, 12427512]. BZDs share the common substructure of a benzene ring fused to a diazepine ring, a seven-membered heterocylic molecule with 2 nitrogens (Goodman & Gilman Chapter 16). Since all the important benzodiazepines contain a 5-aryl substituent and a 1,4-diazepine ring, the term has come to mean the 5-aryl-1,4-benzodiazepines (Goodman & Gilman Chapter 16, Katzung Chapter 22). Modifications to this basic substructure exist; but we will restrict the discussion to those drugs with this basic template, as well as to those used in treatment of central nervous disease disorders. There are more than 20 drugs in this class that are used in central nervous system disorders; a partial list can be seen by clicking on the Benzodiazepine icon in the pathway above. Because of the large number of drugs in this class, this summary is not meant to be exhaustive but, rather, a highlight of the important genes in the benzodiazepine pathway.
The primary target of BZDs is the GABAa receptor, a ligand-gated ion (chloride) channel, activated by γ-aminobutyric acid (GABA) [Articles:11689393, 751612, 18384456] (Goodman & Gilman Chapter 16). Neuronal activity in the brain is regulated by excitatory inputs and inhibitory activity, such as GABAergic inhibitory activity (Goodman & Gilman Chapter 16, Alberts Chapter 11). Stimulation of the inhibitory GABAergic activity, either by endogenous ligands or BZDs or other drugs, results in sedation, amnesia and ataxia, while attenuation of the GABAergic system leads to arousal, anxiety, restlessness, insomnia and exaggerated reactivity (Goodman & Gilman Chapter 16). GABA is normally transported into vesicles by SLC32A1 and stored in the pre-synaptic neuron [Articles:10471414, 12871037]. Upon the arrival of a nerve impulse, the vesicles are triggered to release GABA into the synapse (Step 1 in pathway image), where it can then bind to the GABAa receptor (step 2 in pathway image) (Alberts Chapter 11). The binding of GABA to the GABAa receptor opens the channel, causes the conduction of chloride ions across the neuronal cell membrane (steps 3 and 4), raises the membrane potential of the neuron, which makes it more difficult to depolarize the membrane and hence to excite the cell; this results in inhibition of neuronal firing [Article:11689393] (Goodman & Gilman Chapter 16, Alberts Chapter 11). The termination of the GABAergic signal is achieved by uptake of GABA into the synaptic cell by GABA transporters SLC6A1, SLC6A12, SLC6A13, SLC6A11 (formerly referred to as GAT1, GAT2, GAT3, and GAT4) (step 5). [Articles:9798903, 15829583]. SLC6A1 and SLC6A11 are thought to be the major players in regulating GABAergic neurotransmission in the nervous system [Articles:9798903, 15829583].
The GABAa receptor is a pentameric assembly of homologous GABAa receptor subunits. [Articles:11689393, 751612] (Goodman & Gilman Chapter 16, Katzung Chapter 22). At least 16 different GABAa receptor subunits have been identified, classified into seven subunit families: α, β, γ, δ, ε, θ and pi subunits [Article:18651727] (Goodman & Gilman Chapter 16, Katzung Chapter 22). Additional complexity arises from RNA splice variants of some of these subunits (Goodman & Gilman Chapter 16). The existence of multiple GABAa receptor subunits generates heterogeneity in GABAa receptors and is responsible, in part, for the pharmacological diversity in BDZ effects [Article:15301992] (Goodman & Gilman Chapter 16, Katzung Chapter 22). The differences among BZDs in affinity for the different receptor subtypes, may also be the reason for the different pharmacologic effects [Article:18384456]. The most common GABAa-BDZ receptor in the brain is thought to be composed of 2 subunits of α1; 2 subunits of β2 and 1 subunit of γ2 [Articles:11689393, 12171574, 9426470, 15301992] coded for by GABRA1, GABRB2 and GABRG2 respectively.
The BDZ binding pocket is thought to be in the cleft between subunits α1 and γ2 [Articles:12171574, 9426470], and binding is thought to induce a conformational change in the receptor [Articles:12171574, 11040062]. The BDZ binding pocket is separate from that of the GABA agonist site, which itself is thought to be between the α1 and β2 subunits [Article:9426470]. The general notion of the action of BZDs is that they promote the binding of the major inhibitory neurotransmitter GABA to the GABAa receptors; that is, they do not activate GABAa receptors directly but, instead, are positive allosteric modulators of the effects of GABA [Article:12171574] (Goodman & Gilman Chapter 16) and allow lower concentrations of this neurotransmitter to open the Cl- channels (Alberts Chapter 11). An alternative description of the mechanism of action of BDZs exists. In this latter case, the GABAa receptor is thought to exist in different states, and BDZs (diazepam, in particular, in this study) destablizes the closed state, shifts the equilibrium towards a high affinity open state that allows chloride transport [Article:16783415].
Note that the GABAa receptor is the target of several other drugs and endogenous ligands. Flumazenil (an antagonist) [Article:8043504] and carbolines (an inverse agonist) [Article:9504140] both bind at the BDZ site itself, At other sites of the receptor, barbiturates, ethanol, neurosteroids such as alphoxalone [Article:15959466], anesthetics [Article:15301992], such as propofol [Article:14579514] etomidate [Article:19741491], inhaled anesthetics [Article:11465071] such as isofluorane [Article:14579514] bind. Isofluroane and other inhaled anesthetics also bind to other ion channels [Articles:15101848, 11465071]. Also, the Diazepam Binding Inhibitor (encoded by DBI) is a protein that displaces ligands bound to the BDZ recognition site, including diazepam and flunitrazepam [Articles:3020548, 9504140].
Besides the GABAa receptor, BDZs also bind to the Peripheral Benzodiazepine Receptor (PBR); this receptor consists of several subunits, including the isoquinoline binding protein (encoded by TSPO, and also referred to as a translocator protein); a voltage-dependent anion channel VDAC (VDAC1); an adenine nucleotide transporter ANT (SLC25A4); a PBR-associated protein 1 PRAX-1 (BZRAP1); and another PBR-associated protein PAP7 (ACBD3) [Articles:17692008, 9504140, 12173979, 19133775, 16822554, 16337685]. Benzodiazepines are thought to bind to the subunit encoded by the gene TSPO [Articles:17692008, 19133775, 16822554, 16337685]. This receptor is expressed in abundance in many peripheral organs and tissues as well as in the central nervous system, in the latter case, in glia cells [Articles:9504140, 12173979]. Diazepam, midazolam and flunitrazepam bind equally well to both the GABAa receptor and the peripheral BDZ receptor [Articles:9504140, 12173979]. Studies have shown that the Peripheral Benzodizepine Receptor may play an important role in the human immune system and take part in the pathophysiological processes of several nervous system disorders [Articles:9504140, 12173979]. The Diazepam Binding Inhibitor protein is a putative ligand for TSPO [Articles:17692008, 16337685].
The use of BDZs may lead to physical and psychological dependence. Abuse and dependence of BDZs have been reported. The risk of dependence increases with higher doses and longer term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of BDZs have been reported. Once physical dependence to BDZs have developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy (please see the diazepam DailyMed drug label)
Pharmacokinetics and Pharmacogenomics
While the BDZs share a common template, and all bind to the GABAa receptor, they have different physiochemical properties, most notably lipid solubility, which influence their pharmacokinetics, as well as their rate of absorption and diffusion [Article:18384456]. The two principal pathways of the BDZ biotransformation involve hepatic microsomal oxidation, N -dealkylation or aliphatic hydroxylation and glucuronide conjugation [Article:18175099] (Katzung Chapter 22). Pharmacogenomics studies of BDZs have focused on their metabolizing enzymes. Please see the benzodiazepine pharmacokinetic pathway for more details.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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Entities in the Pathway
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|Peripheral BDZ receptor (ACBD3, BZRAP1, DBI, SLC25A4, TSPO, VDAC1)||Peripheral BDZ receptor (ACBD3, BZRAP1, DBI, SLC25A4, TSPO, VDAC1)||benzodiazepine derivatives|
|GABAa receptor inactive (GABRA1, GABRB2, GABRG2)||GABAa receptor active (GABRA1, GABRB2, GABRG2)||benzodiazepine derivatives, GABA||11689393, 12171574, 15301992, 9426470|
|Cl-||Cl-||GABAa receptor active (GABRA1, GABRB2, GABRG2)|
|GABA||GABA||SLC6A1, SLC6A11, SLC6A12, SLC6A13||15829583, 9798903|
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